Title Razvoj i optimiranje nazalne depozicije inovativnih farmaceutskih oblika kortikosteroida Title (english) Development and nasal deposition optimisation of innovative pharmaceutical forms of corticosteroids Author Laura Nižić Nodilo Mentor Anita Hafner (mentor)Committee member Jasmina Lovrić (predsjednik povjerenstva)Committee member Ana Mornar Turk (član povjerenstva)Committee member Marjana Dürrigl (član povjerenstva)Granter University of Zagreb Defense date and country 2022-06-27, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Universal decimal classificationUDC ) 615 - Pharmacology. Therapeutics. Toxicology Abstract Nazalna primjena lijeka uobičajena je u liječenju lokalnih oboljenja nosne sluznice. Istražuje se i kao alternativni put sistemske primjene lijekova, a pruža mogućnost i izravne dostave lijeka u središnji živčani sustav. Ograničenja nazalne primjene lijeka uključuju otežanu dostavu lijeka u ciljno područje te mukocilijarni klirens koji skraćuje vrijeme kontakta lijeka i nosne sluznice. Nazalna primjena kortikosteroida česta je u liječenju bolesti nosne sluznice i paranazalnih sinusa, a u novije vrijeme predlaže se i u liječenju neuroupalnih procesa. U okviru ovog doktorskog rada, primjenjujući načela kakvoće utemeljene kroz dizajn, razvijena su tri inovativna in situ gelirajuća sustava s uklopljenim kortikosteroidom za nazalnu primjenu u obliku spreja: (i) in situ gelirajuća mikrosuspenzija flutikazonpropionata (FP-a), (ii) in situ gelirajuća nanosuspenzija FP-a pripravljena uz vlažno mljevenje te (iii) praškasti sustav mikrosfera s natrijevim deksametazonfosfatom (NDF-om) i inertnog nosača. Provedena je njihova temeljita fizičko-kemijska i biofarmaceutska karakterizacija. Polimerni sastav in situ gelirajućih mikro- i nanosuspenzija FP-a osigurao je pseudoplastično ponašanje, prikladnost za primjenu raspršivanjem (tj. prikladnu veličinu raspršenih kapljica i kut raspršenja) te svojstvo geliranja u kontaktu sa simuliranim nosnim fluidom (SNF). Mikrosfere s NDF-om, pripravljene sušenjem raspršivanjem, karakterizirane su velikom uspješnošću uklapanja lijeka, odgovarajućim sadržajem ostatne vlage te sposobnošću bubrenja u SNF-u pri čemu nastaje gel. Smjese mikrosfera s NDF-om i inertnog nosača bile su homogene te boljih svojstava tečenja i užeg kuta raspršenja od samih mikrosfera. Postignuta je uspješna depozicija sva tri farmaceutska oblika u ciljnoj regiji nosne šupljine, ovisno o željenom učinku. Razvijeni farmaceutski oblici karakterizirani su boljom mukoadhezivnošću u usporedbi s konvencionalnim oblicima. Oslobađanje lijeka iz svih razvijenih oblika bilo je prikladno za nazalnu primjenu. Nanonizacija FP-a rezultirala je većom mukoadhezivnošću formulacije te većom topljivošću i brzinom oslobađanja FP-a iz in situ gela, pružajući mogućnost smanjenja primijenjene doze. Svim sustavima potvrđena je biokompatibilnost in vitro na modelu Calu-3 stanica te fizičko-kemijska stabilnost. Praškasti sustav s NDF-om pokazao je potencijal poboljšanja permeacije lijeka kroz nazalni epitel. Prilagođavanjem procesnih, formulacijskih i/ili parametara primjene korištenjem dizajna eksperimenta razvijeni su inovativni farmaceutski oblici kortikosteroida s potencijalom produljenog zadržavanja na mjestu primjene, povoljnih biofarmaceutskih svojstava i optimirane depozicije u nosnoj šupljini.
Abstract (english) Nasal drug delivery is well estabilshed in the treatment of local nasal mucosa diseases. It is also being investigated as an alternative route of systemic drug delivery, as well as the possibility of direct drug delivery to the central nervous system. Limitations of nasal drug administration include difficult drug delivery to the target area and mucociliary clearance, which shortens the contact time between the drug and the nasal mucosa. Nasal use of corticosteroids is common in the treatment of diseases of the nasal mucosa and paranasal sinuse. Recently it has been suggested in the treatment of neuroinflammatory processes. Within this doctoral thesis, employing quality by design principles, three innovative in situ gelling pharmaceutical forms of corticosteroid for nasal spray application have been developed: (i) in situ gelling microsuspension of fluticasone propionate (FP), (ii) in situ gelling nanosuspension of FP prepared by wet media milling; and (iii) powder platform consisting of dexamethasone sodium phosphate (DSP)-loaded microspheres blended with an inert carrier. Thorough physicochemical and biopharmaceutical characterization of developed systems was performed. The polymer composition of the in situ gelling micro- and nanosuspensions of FP ensured shear thinning behavior, suitability for administration as a spray (i.e., suitable droplet size and spray angle), and immediate gelling in contact with simulated nasal fluid (SNF). Microspheres with DSP, prepared by spray drying, are characterized by high drug entrapment efficiency, adequate residual moisture content, and good swelling ability in SNF, forming a gel. Blends of microspheres with DSP and inert carrier were homogeneous and had better flow properties and a narrower spray cone angle than the microspheres alone. Successful deposition of all three pharmaceutical forms in the target region of the nasal cavity model was achieved, depending on the desired effect. Developed pharmaceutical forms are characterized by better mucoadhesiveness compared to conventional forms. Drug release from all developed forms was suitable for nasal administration. Nanonization of FP resulted in greater mucoadhesiveness of the formulation and increased solubility and release rate of FP from the in situ gel, providing the possibility of reducing the applied dose. Biocompatibility on the in vitro Calu-3 cell model and the physicochemical stability was confirmed for all developed formulations. The powder system with DSP showed the potential to improve drug permeation through the nasal epithelium. By varying process, formulation and/or administration parameters, employing design of experiments, innovative pharmaceutical forms of corticosteroids with the potential for prolonged retention at the site of administration, favourable biopharmaceutical properties and optimized deposition in the nasal cavity have been successfully developed.
Keywords
in situ gelirajući sustav
nanosuspenzija
mikrosfere
sušenje raspršivanjem
flutikazonpropionat
natrijev deksametazonfosfat
nazalna depozicija
Keywords (english)
in situ gelling system
nanosuspension
microspheres
spray drying
fluticasone propionate
dexamethasone sodium phosphate
nasal deposition
Language croatian URN:NBN urn:nbn:hr:163:205147 Promotion 2022 Study programme Title: Pharmacy and biochemistry Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2022-07-25 15:05:15
